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| Status |
Public on Jun 04, 2020 |
| Title |
c-Rel gain in B cells dose-dependently drives germinal center reactions and autoantibody production in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Single nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpress c- Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictate expansion of germinal center (GC) B cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescues terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GC B cells transcription-independent regulation produces the highest c-Rel protein levels amongst B cell subsets. In c-Rel overexpressing GC B cells this causes enhanced nuclear translocation, a profoundly altered transcriptional program and increased proliferation. Finally, we provide the first link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells causes autoantibody production and renal immune complex deposition.
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| Overall design |
For RNA sequencing experiments 8 mice per genotype were immunized i.p. with SRBC. Desired splenocyte populations were pre-separated by MACS followed by flow-cytometry- based cell sort of 1000 cells per sample into 96-well-plates containing TCL buffer (Qiagen) (naïve B cells: pre-MACS IgD+CD43+, sort IgDhiIgMlo; GC B cells: pre-MACS IgD-CD43-, sort B220+IgD-CD38loCD95hiGL7+; PC: pre-MACS CD138+, sort B220loCD138+).
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| Contributor(s) |
Ziegenhain C, Enard W |
| Citation(s) |
32191641 |
| |
| Submission date |
Jan 06, 2020 |
| Last update date |
Jun 04, 2020 |
| Contact name |
Christoph Ziegenhain |
| E-mail(s) |
[email protected]
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| Organization name |
Ludwig-Maximilians University Munich
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| Department |
Department Biology II
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| Lab |
Anthropology & Human genomics
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| Street address |
Großhaderner Str. 2
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| City |
Martinsried |
| State/province |
Bavaria |
| ZIP/Postal code |
82152 |
| Country |
Germany |
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| Platforms (1) |
| GPL18480 |
Illumina HiSeq 1500 (Mus musculus) |
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| Samples (48)
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| Relations |
| BioProject |
PRJNA599120 |
| SRA |
SRP239544 |
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